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The Pal3 Promoter Sequence Is Critical for the Regulation of Human Renin Gene Transcription by Peroxisome Proliferator-Activated Receptor-

Institute of Physiology, University of Regensburg, D-93040 Regensburg, Germany

Address all correspondence and requests for reprints to: Dr. Vladimir T. Todorov, Institute of Physiology, University of Regensburg, D-93040 Regensburg, Germany. E-mail: vladimir.todorov{at}vkl.uni-regensburg.de.

We recently reported that human renin gene transcription is stimulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)- in the renin-producing cell line Calu-6. The effect of PPAR was mapped to two sequences in the renin promoter: a direct repeat hormone response element (HRE), which is related to the classical PPAR response element (PPRE) and a nonconsensus palindromic element with a 3-bp spacer (Pal3). We now find that PPAR binds to the renin HRE. Neither the human renin HRE nor the consensus PPRE was sufficient to attain the maximal stimulation of renin promoter activity by the PPAR agonist rosiglitazone. In contrast, the human renin Pal3 element mediates both the full PPAR-dependent activation of transcription and the PPAR-driven basal renin gene transcription. The human renin Pal3 sequence was found to selectively bind PPAR and the retinoid X receptor- from Calu-6 nuclear extracts. This is in contrast to the consensus PPRE, which can bind other nuclear proteins. PPAR knockdown paradoxically did not attenuate the stimulation of the endogenous renin gene expression by rosiglitazone. Similarly, a deficiency of PPAR did not attenuate the activation of the minimal human renin promoter, which contains the endogenous Pal3 motif. However, when the human renin Pal3 site was replaced by the consensus PPRE sequence, PPAR knockdown abrogated the effect of rosiglitazone on renin promoter activity. Thus, the human renin Pal3 site appears to be critical for the PPAR-dependent regulation of gene expression by mediating maximal transcription activation, particularly at the low cellular level of PPAR.

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